2-Aminobenzodiazepine-5-ones

ABSTRACT

Compounds of the class of 2-amino-3,4-dihydro-4-loweralkyl-5H-1,4-benzodiazepine-5-ones useful as CNS depressants and hypotensive agents.

DESCRIPTION OF THE INVENTION

The novel 2-aminobenzodiazepine-5-ones of this invention may bestructurally represented by the formula: ##STR1## wherein: R is a memberselected from the group consisting of hydrogen, arylloweralkyl,indolylloweralkyl, diloweralkylaminoloweralkyl, and aryl;

R₁ is a member selected from the group consisting of hydrogen and aryl,preferably phenyl;

R₂ is loweralkyl, preferably methyl; and

R₃ is a member selected from the group consisting of hydrogen, halo,nitro, loweralkoxy, and loweralkyl; preferably hydrogen and halo;

Provided that:

When said R is hydrogen, then said R₁ is aryl.

As used herein, "aryl" includes phenyl, trifluoromethyl-phenyl andsubstituted phenyl. "Substituted phenyl", as used herein, means phenylwith from one to three substituents each selected from the groupconsisting of halo, loweralkyl, hydroxy, and loweralkoxy. "Loweralkyl"and "loweralkoxy" may be straight or branched chained and have from oneto five carbon atoms. The term "halo" is generic to chloro, bromo, iodo,and fluoro, preferably chloro.

The therapeutically active non-toxic acid addition salts of the subjectcompounds are also embraced within the scope of this invention.

The novel 2-aminobenzodiazepine-5-ones of formula (I) are readilyobtained by the reaction of an appropriate benzodiazepine-2,5-dione offormula (II) with an unsubstituted amine or an appropriately substitutedprimary amine of formula (III), wherein R is as previously defined, inthe presence of TiCl₄ in a suitable aprotic organic solvent. The amine(III) is in stoichiometric excess of the benzodiazepine-2,5-dione (II),preferably at a ratio of 5:1, respectively. The TiCl₄ is also preferablyin stoichiometric excess. Suitable organic solvents include ethers, suchas, for example, tetrahydrofuran (THF), dioxane, monoglyme and the like.

It should be noted that in the case of formation of the formula (I)compounds wherein R is: ##STR2## IN WHICH N IS AN INTEGER FROM 1 TO 3,THE APPROPRIATE AMINE IS A BENZYLOXYPHENLOWERALKYL AMINE OF THE FORMULA:##STR3## The resulting novel intermediates,2-(benzyloxyphenloweralkylamino)-benzodiazepine-5-ones, of the formula:##STR4## are then subjected to catalytic hydrogenation, for example, bytreatment with H₂ in the presence of a metallic catalyst such aspalladium, platinum, Raney nickel and the like, preferably underpressure, in order to debenzylate such intermediates and yield thedesired hydroxyphenylloweralkyl derivatives of formula (I).

The reaction mixture may be heated, preferably under reflux, to enhancethe rate of reaction.

An alternate method of synthesis of the subject compounds (I) involvesreacting the formula (II) benzodiazepine-2,5-diones with P₂ S₅ in asuitable organic solvent such as, for example, pyridine and the like,and ethers such as, for example, THF, dioxane, monoglyme and the like,to form as novel intermediates, the 2-thiobenzodiazepine-2,5-diones offormula (IV). From this point either of two routes may be taken to formthe subject compounds (I).

Compounds of formula (IV) may be transformed into those of formula (I)directly by reaction with an appropriate amine of formula (III). Theamine is used preferably in slight stoichiometric excess. The reactantsare utilized either without solvent if the amine is a liquid or with asuitable organic solvent such as, for example, acetonitrile, pyridineand the like, and ethers such as, for example, THF, dioxane and thelike. Elevated temperatures may be advantageously employed to enhancethe rate of reaction.

An alternate route involves methylating the formula (IV) compounds toanother set of novel intermediates, the2-methylthiobenzodiazepine-5-ones of formula (IVa). Suitable methylatingagents include, for example, CH₃ I/NaH in an aromatic hydrocarbonsolvent, for example, benzene, toluene, xylene and the like,dimethylsulfate (DMS)/aqueous NaOH, and the like. Another route ofmethylation employs methyl fluorosulfonate as the methylating agent in achlorinated hydrocarbon solvent such as, for example, chloroform,methylene dichloride and the like. The methylated product (IVa) is thentreated with an appropriate amine (III) as heretofore described to yieldthe desired final products (I).

The foregoing reactions may be schematically illustrated by thefollowing diagram: ##STR5##

The diones of formula (II) wherein R₁ is hydrogen are described in theliterature. However, those diones of formula (II) having an aryl group(Ar) as R₁ are novel. They may be prepared via a two step syntheticroute. An appropriate o-nitrobenzoyl chloride of formula (V) is reactedwith a cooled solution (0°-10° C) of, preferably, an equivalent amountof an appropriate α-aryl-N(loweralkyl)amino acid of formula (VI) in thepresence of a suitable base, such as an alkali metal hydroxide, toneutralize the acid liberated during the course of the reaction. Shouldan acid addition salt form of (VI) be initially employed, an additionalequivalent of base is preferably used to neutralize said salt to thecorresponding free base form. The resultant solution of the alkali metalsalt of (VII) is then treated with an appropriate acid such as, forexample, a concentrated mineral acid, e.g. HCl, HBr and the like, toprecipitate out the novel acid precursor,β-loweralkyl-o-nitro-α-arylhippuric acid of formula (VII). This acidprecursor is then subjected to catalytic hydrogenation, e.g., byreaction with H₂ in 95% ethanol in the presence of a catalytic amount ofplatinum oxide in a Parr hydrogenator, to give the diones of formula(II) wherein R₁ is aryl.

The reaction described above may be illustrated as follows: ##STR6##

Another method for the synthesis of the subject compounds (I), wherein Ris hydrogen and R₁ is aryl, also begins with the formula (V)o-nitrobenzoyl chlorides. The addition of (V) to a cooled solution(0°-10° C) of an equivalent amount of an appropriateN-loweralkyl-α-arylglycinitrile of formula (VIII) and a strong organicbase such as, for example, triethylamine, N-methylpiperidine and thelike, in an appropriate organic solvent, such as, for example,1,2-dichloroethane, chloroform, dimethoxyethane and the like, producesthe novel intermediate, β-loweralkyl-o-nitro-α-aryl-hippuronitrile offormula (IX). After the reactants have been mixed together, thetemperature may be elevated to ambient temperature. This novelintermediate (IX) is also catalytically hydrogenated under conditionspreviously described to form another intermediate, the3-aryl-1-hydroxy-2-imino-4-loweralkyl-1,2,3,4-tetrahydro-5H-1,4-benzodiazepine-5-oneof formula (X). A solution of (X) in a suitable organic solvent such as,for example, a loweralkanol and the like, is then added to a solution ofsodium dithionite (Na₂ S₂ O₄), the latter preferably being in a two-foldstoichiometric excess, to produce the subject compounds of formula (I)with R as hydrogen and R₁ as aryl. The reaction mixture may be heated,preferably under reflux conditions, to enhance the rate of reaction. Thereaction scheme described above may be illustrated as follows: ##STR7##

The compounds of formula (I) may be converted to the correspondingtherapeutically active non-toxic acid addition salt form by reactionwith an appropriate acid, such as, for example, an inorganic acid, suchas, a hydrohalic acid, e.g., hydrochloric, hydrobromic, or hydroiodicacid, and sulfuric acid, nitric acid, phosphoric acid and the like; oran organic acid, such as, acetic, propionic, glycolic, lactic, pyruvic,malonic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic,cinnamic, mandelic, methanesulfonic, ethanesulfonic,hydroxyethane-sulfonic, benzenesulfonic, p-toluenesulfonic,cyclohexanefulfamic, salicyclic, p-aminosalicyclic, 2-phenoxybenzoic,2-acetoxybenzoic and the like acids. Conversely, the salt form can beconverted by treatment with alkali into the free base form.

The compounds (I) of this invention are useful as CNS depressants and/orhypotensive agents. Specifically, the subject compounds wherein R isdihydroxyphenloweralkyl (dopamine analogs) or indolylloweralkyl(tryptamine analogs) have been observed to produce a decrease in bloodpressure of about 40-120 mm Hg when administered i.v. to anesthetizeddogs in a dose of about 10 mg/kg body weight. Compounds of formula (I)in which R is (i) arylloweralkyl other than the dihydroxyphenloweralkyldopamine analogs mentioned above, or (ii) diloweralkyl-aminoloweralkyl,or (iii) the compounds wherein R is hydrogen and R₁ is, necessarily,aryl, possess useful central nervous system (CNS) depressant propertiesas demonstrated in one or more of the following tests indicative of suchactivity in laboratory animals. The remaining formula (I) compoundspossess both the aforementioned hypotensive property and said CNSdepressant properties as demonstrated in one or more of the followingtests.

Test A:

A muscle-relaxant assay as judged by the effect of the compound to betested on strychnine-induced seizures as described by M.J. Orloff etal., Proc. Soc. Exp. Biol. and Med. 70, 254 (1949) as modified by G.Chen and B. Bohner, J. Pharmacol. and Expt. Therap. 117, 142 (1956). Theanti-strychnine activity of the compound to be tested is observed inmice at oral doses of about 25-500 mg./kg. body weight by determiningthe effect of the compound on the seizure threshold induced bystrychnine.

Test B:

A muscle-relaxant assay as judged by the effect of the compound to betested on metrazole-induced seizures as described by M.J. Orloff et al.,Proc. Soc. Exp. Biol. and Med. 70, 254 (1949). The anti-metrazoleactivity of the compound to be tested is observed in mice at oral dosesof about 25-500 mg./kg. body weight by determining the effect of thecompound on the seizure thresholds induced by metrazole.

Test C:

A anti-convulsant assay which is a supra-maximal electroshock seizuretest as described by E. A. Swinyard et al., J. Pharmacol. Expt. Therap.106, 319 (1952). In this assay, the compound to be tested isadministered orally to mice at doses generally ranging from 25-500mg./kg. body weight and the blocking effect of the compound on the tonicextensor seizure following the application of a supramaximal current tothe animal is observed.

Test D:

A mouse behavorial assay as described by S. Irwin, Gordon ResearchConference on Medicinal Chemistry, 1959, p. 133. In this assay, suchsymptoms as ataxia, decrease in motor activity and loss or rightingreflex are observed after intraperitoneal (i.p.) administration in miceof the compound to be tested at doses ranging from 10-300 mg./kg. bodyweight.

The following examples are intended to illustrate, but not to limit, thescope of the present invention.

EXAMPLE I

A. 7-Chloro-3,4-dihydro-4-methyl-2-thio-1H-1,4-benzodiazepine-2,5-dione:

A stirred mixture of 67.4 g (0.30m) of7-chloro-3,4-dihydro-4-methyl-1-H-1,4-benzodiazepine-2,5-dione and 26.7g (0.12m) of phosphorous pentasulfide in 750 ml of pyridine is heated ona steam bath for 18 1/2 hr. The reaction mixture is concentrated todryness in vacuo and partitioned between 300 ml of chloroform and 300 mlof cold 10% NaOH. The layers are separated and the organic (lower) layeris extracted with three 100 ml portions of 10% NaOH. The combinedaqueous extracts are cooled in an ice bath and acidified with 110 ml ofconcentrated HCl causing the product to precipitate. The solid isfiltered off, washed with water, and recrystallized fromdimethylformamide-water to give a bright yellow solid. A secondrecrystallization from dimethylformamide-water (30:1) gives the pureproduct,7-chloro-3,4-dihydro-4-methyl-2-thio-1H-1,4-benzodiazepine-2,5-dione, asa yellow solid, m.p. (264s) 271°-275° C (dec).

B.2-Benzylamino-7-chloro-3,4-dihydro-4-methyl-5H-1,4-benzodiazepine-5-one:

A stirred mixture of 6.74 g (0.028 m) of7-chloro-3,4-dihydro-4-methyl-2-thio-1H-1,4-benzodiazepine-2,5-dione and3.00 g (0.028 m) of benzyl amine in 100 ml of acetonitrile is heated toreflux while sweeping with nitrogen for 3 hr. The resulting solution isfiltered to clarify and then concentrated to dryness in vacuo giving 9.2g of an oily residue which is dissolved in 100 ml of benzene andextracted with five 20 ml portions of 10% NaOH and one 20 ml portion ofsaturated NaCl solution. The benzene solution is dried (anhydrous)MgSO₄) and concentrated to dryness in vacuo giving an oil whichcrystallizes when triturated with ether. The resulting solid is groundwell under ether and the slurry is filtered to give2-benzylamino-7-chloro-3,4-dihydro-4-methyl-5H-1,4-benzodiazepine-5-one,m.p. (153 s) 158°-160° C. Two recrystallizations from ethylacetate-ether give the pure product, m.p. 158°-159.5° C.

EXAMPLE II

The procedure of Example I is repeated except that an equivalent amountof each of p-trifluoromethylbenzyl amine, 2,4,6-tribromobenzyl amine and2,4-dimethylbenzyl amine is substituted for the benzyl amine used inpart B to yield, as respective products, the following:

2-(p-trifluoromethylbenzylamino)-7-chloro-3,4-dihydro-4-methyl-5H-1,4-benzodiazepine-5-one;

2-(2,4,6-tribromobenzylamino)-7-chloro-3,4-dihydro-4-methyl-5H-1,4-benzodiazepine-5-one;and

2-(2,4-dimethylbenzylamino)-7-chloro-3,4-dihydro-4-methyl-5H-1,4-benzodiazepine-5-one.

EXAMPLE III

3,4-Dihydro-4-methyl-2-β-phenethylamino-5H-1,4-benzodiazepine-5-one:

A solution of 17.0 g (0.14m) of β-phenethylamine in 100 ml drytetrahydrofuran (THF) is added to a stirred suspension of 6.65 g (0.035m) of 3,4-dihydro-4-methyl-5H-1,4-benzodiazepine2,5-dione in 125 ml dryTHF over a 3 minute period under a nitrogen atmosphere. A solution of7.31 g. (4.25 ml) (0.0385m) of titanium tetrachloride in 225 ml dry THF[CAUTION! Violent exothermic reaction occurs when TiCl₄ is added to THFwith copious evolution of fumes.] is added over a 30 minute period tothe stirred reaction. Stirring is continued at room temperature for 30minutes and at reflux overnight. The reaction is cooled to roomtemperature and an additional 4.24 g (0.035 m) of phenethylamine in 25ml dry THF is added over a 5 minute period and the reaction stirred foran additional 5 hour at room temperature. Then 95 ml of H₂ O is added(dropwise at first and then in a steady stream), the slurry is filteredand the filtrate is evaporated to dryness in vacuo giving a mixture ofsolid and oil which is extracted with ether and then ethyl acetateleaving behind phenethylamine hydrochloride. The soluble portion isevaporated to dryness in vacuo and redissolved in CHCl₃. The chloroformsolution is extracted with 10% HCl and then with 10% NaOH, dried andevaporated to dryness in vacuo giving an oily residue. The acid solutionabove is made basic with 50% NaOH and extracted with CHCl₃. Thischloroform solution is dried and evaporated to dryness in vacuo givingan oil. Both fractions of oil crystallize when treated with ether givingthe crude product,3,4-di-hydro-4-methyl-2-β-phenethylamino-5H-1,4-benzodiazepine-5-one.Two recrystallizations from ethyl acetate gives the pure product as softwhite needles, m.p. 150°-151° C.

EXAMPLE IV

The procedure of Example III is repeated except that an equivalentamount each of p-butyl-β-phenethyl amine, 2,4,6-trimethyl-β-phenethylamine, and 3-chloro-β-phenethyl amine is substituted for the β-phenethylamine used therein to yield, as respective products, the following:

2-(p-butyl-β-phenethylamino)-3,4-dihydro-4-methyl-5H-1,4-benzodiazepine-5-one;

2-(2,4,6-trimethyl-β-phenethylamino)-3,4-dihydro-4-methyl-5H-1,4-benzodiazepine-5-one;

2-(3-chloro-β-phenethylamino)-3,4-dihydro-4-methyl-5H-1,4-benzodiazepine-5-one.

EXAMPLE V

7-Chloro-3,4-dihydro-4-methyl-2-phenethylamino-5H-1,4-benzodiazepine-5-one:

A mixture of 13.24 g (0.055 m) of7-chloro-3,4-dihydro-4-methyl-2-thio-5H-1,4-benzodiazepine-2,5-dioneprepared according to the method described in Example I-A, and 6.06 g(0.05 m) of β-phenethylamine in 150 ml of acetonitrile is stirred andrefluxed for 25 hour. The reaction mixture is cooled and filtered togive the crude product,7-chloro-3,4-dihydro-4-methyl-2-phenethylamino-5H-1,4-benzodiazeine-5-one.Recrystallization from ethyl acetate and from ethanol/ether gives thepure product, m.p. 196.5°-198° C.

EXAMPLE VI

By utilizing an equivalent amount of 4-hydroxy-3,5-dimethyl-β-phenethylamine for the phenethyl amine in the procedure of Example V,7-chloro-3,4-dihydro-2-(4-hydroxy-3,5-dimethylphenethylamino)-4-methyl-5H-1,4-benzodiazepine-5-one is obtained as theproduct.

EXAMPLE VII

7-Chloro-3,4-dihydro-2-(3,4-dimethoxy-β-phenethylamino)-4-methyl-5H-1,4-benzodiazepine-5-one:

A solution of 25.4 g (0.14 m) of redistilled homoveratryl amine in 100ml of dry tetrahydrofuran is added in a slow stream over a 5 minuteperiod to a stirred suspension of 7.87 g (0.035 m) of7-chloro-3,4-dihydro-4-methyl-5H-1,4-benzodiazepine-2,5-dione in 150 mlof dry tetrahydrofuran under a nitrogen atmosphere. Then a solution of7.96 g (4.63 ml; 0.042 m) of titanium tetrachloride in 450 ml of drytetrahydrofuran [CAUTION! A vigorous, exothermic reaction occurs whenthe titanium tetrachloride is added to the tetrahydrofuran and copiousfumes are emitted.] is added dropwise to the stirred reaction mixtureover a 60 minute period without cooling. Stirring is continued for 1hour at room temperature and at reflux for 21 hour. The reaction mixtureis allowed to cool to about 30° C and an additional 6.35 g (0.035 m) ofhomoveratrylamine in 25 ml of dry tetrahydrofuran is added over a 15minute period. Stirring is continued for 5 hours more. Then 95 ml H₂ Ois added, the slurry is filtered, and the filtrate concentrated todryness in vacuo giving an oily residue. This residue is dissolved inchloroform, extracted with 10% hydrochloric acid and 10% sodiumhydroxide, dried and concentrated to dryness in vacuo to give an oil(which crystallizes on standing). Recrystallization from ethyl acetategives the solid product,7-chloro-3,4-dihydro-2-(3,4-dimethoxy-β-phenethylamino)-4-methyl-5H-1,4-benzodiazepine-5-one,melting at 175°-178° C. The acid extract above is made basic andextracted with chloroform. The chloroform solution is dried andconcentrated to dryness in vacuo giving an oil which crystallizes whentreated with ether. Filtration of this mixture leads to recovery of asolid product melting at 150°-159° C. The two batches of solid productare combined and recrystallized twice from alcohol-ether giving the pureproduct,7-chloro-3,4-dihydro-2-(3,4-dimethyl-β-phenethylamino)-4-methyl-5H-1,4-benzodiazepine-5-one,a white solid with m.p. 177.5°-179.0° C.

EXAMPLE VIII

The procedure of Example VII is repeated except that an equivalentamount each of 3-methoxyphenethyl amine, 3,4-dimethoxy-2-methylphenethylamine, and 4-methoxyphenethyl amine is substituted for the homoveratrylamine used therein to yield, as respective products, the following:

7-chloro-3,4-dihydro-2-(3-methoxyphenethylamino)-4-methyl-5H-1,4-benzodiazepine-5-one;

7-chloro-3,4-dihydro-2(3,4-dimethoxy-2-methylphenethylamino)-4-methyl-5H-1,4-benzodiazepine-5-one;and

7-chloro-3,4-dihydro-2(4-methoxyphenethylamino)-4-methyl-5H-1,4-benzodiazepine-5-one.

EXAMPLE IX

3,4-Dihydro-2-(3,4-dihydroxyphenethylamino)-4-methyl-5H-1,4-benzodiazepine-5-oneHydrochloride Hemimethanolate:

A mixture of 8.42 g (0.035 m) of7-chloro-3,4-dihydro-4-methyl-2-thio-1H-1,4-benzodiazepine-2,5-dione and11.67 g (0.035m) of 3,4-dibenzyloxy-β-phenethylamine in 150 ml ofacetonitrile is stirred and refluxed for 17 hours. The reaction mixtureis concentrated to dryness in vacuo to give an oily residue. Thisresidue is dissolved in benzene and washed with 1N sodium hydroxidesolution and 3N hydrochloric acid to give a gummy residue. This gum isdissolved in methanol, diluted with an equal volume of benzene, treatedwith charcoal, filtered and concentrated to dryness in vacuo to givecrude7-chloro-2-(3,4-dibenzyloxyphenethylamino)-3,4-dihydro-4-methyl-5H-1,4-benzodiazepine-5-one.The free base is converted in ethanol/ether, to the hydrochloride saltto give a white solid, with m.p. (153 softens) 158°-162° C.

A mixture of 11.34 g (0.0197m) of7-chloro-2-(3,4-di-benzyloxyphenethylamino)-3,4-dihydro-4-methyl-5H-1,4-benzodiazepine-5-onehydrochloride and 10% palladium on charcoal catalyst in 250 ml ofabsolute methanol is hydrogenated until no more hydrogen is absorbed.The catalyst is removed by filtration and the filtrate is concentratedto dryness in vacuo to give crude3,4-dihydro-2-(3,4-dihydroxyphenethylamino)-4-methyl-5H-1,4-benzodiazepine-5-onehydrochloride hemi methanolate. Several recrystallizations fromethanol/ether give the pure product, m.p. 179°-180° C dec.

EXAMPLE X

The procedure of Example IX is repeated except that an equivalent amountof 2,4,5-tribenzyloxyphenethyl amine is substituted for the3,4-dibenzyloxyphenethyl amine used therein to yield the product.

3,4-dihydro-4-methyl-2-(2,4,5-trihydroxyphenethylamino)-5H-1,4-benzodiazepine-5-one.

EXAMPLE XI

A.7-Chloro-3,4-dihydro-4-methyl-2-methylthio-5H-1,4-benzodiazepine-5-one:

A solution of 0.69 g (0.0055 m) of dimethyl sulfate in 2.5 ml ofmethanol is added dropwise at room temperature to a stirred mixture of1.20 g (0.005 m) of7-chloro-3,4-dihydro-4-methyl-2-thio-1H-1,4-benzodiazepine-2,5-dioneprepared according to the method described in Example I-A in 6.0 ml 1Nsodium hydroxide solution and 7.5 ml of methanol. The reaction mixtureis stirred at room temperature for 45 minutes after which time 10 ml ofwater is added and the pH adjusted to 11 by the addition of 3.0 ml 5Nsodium hydroxide solution. The mixture is cooled and the precipitateremoved by filtration. The solid is washed with water and dried to giveyellow compound,7-chloro-3,4-dihydro-4-methyl-2-methylthio-5H-1,4-benzodiazepin-5-one,m.p. 124°-127° C.

B.7-Chloro-2-(2',6'-dichloroanilino)-3,4-dihydro-4-methyl-5H-1,4-benzodiazepine-5-one:

A mixture of 20.38 g (0.08m) of7-chloro-3,4-dihydro-4-methyl-2-methylthio-5H-1,4-benzodiazepine-5-oneand 64.81 g (0.40m) of 2,6-dichloroaniline is stirred and heated to 225°for 1 1/2 hr. The reaction mixture is cooled to room temperature andcrystallized from ether to give the crude product,7-chloro-2-(2',6'-dichloroanilino)-3,4-dihydro-4-methyl-5H-1,4-benzodiazepine-5-one,m.p. (230) 240°-245°. Recrystallization from acetone-ether and frommethanol-isopropanol gives white solid with m.p. 247°-249.5°.

EXAMPLE XII

7-Chloro-3,4-dihydro-2-[3-(dimethylamino)-propylamino]-4-methyl-5H-1,4-benzodiazepine-5-oneDihydrochloride:

A stirred mixture of 10.7 g (0.045 m) of7-chloro-3,4-dihydro-4-methyl-2-thio-1H-1,4-benzodiazepine-2,5-dioneprepared as described in Example I-A, and 5.51 g (0.054m) ofdimethylaminopropylamine in 100 ml of acetonitrile is heated on a steambath at reflux, while sweeping with nitrogen, for 4 1/2 hours. Theresulting solution is concentrated to dryness in vacuo giving an oilyresidue which is then dissolved in anhydrous ether. A saturated solutionof ethereal HCl is added to precipitate the dihydrochloride salt. Thesolution is filtered and the solid is recrystallized once frommethanol-ether and again from methanol giving the light yellow solidproduct,7-chloro-3,4-dihydro-2-[3-(dimethylamino)-propylamino]-4-methyl-5H-1,4-benzodiazepine-5-one;m.p. 261°-264° C (dec.)

EXAMPLE XIII

Utilizing an equivalent amount of diethylaminoethylamine in place ofdimethylaminopropylamine in the procedure of Example XII results in theproduct:

7-Chloro-3,4-dihydro-2-[2-(diethylamino)ethylamino]-4-methyl-5H-1,4-benzodiazepine-5-onedihydrochloride.

EXAMPLE XIV

7-Chloro-3,4-dihydro-2-[2-(3-indolylethyl)amino]-4-methyl-5H-1,4-benzodiazepine-5-one:

A mixture of 8.43 g (0.035 m) of7-chloro-3,4-dihydro-4-methyl-2-thio-1H-1,4-benzodiazepine-2,5-dione and5.61 g (0.035 m) of tryptamine in 150 ml of acetonitrile is stirred andrefluxed for 4 1/2 hours. The reaction mixture is concentrated to about80 ml, cooled and filtered to give the solid product. Recrystallizationfrom methyl ethyl ketone/ether (125 ml: 375 ml) gives the pure product,7-chloro-3,4-dihydro-2-[2-(3-indolylethyl)amino]-4-methyl-5H-1,4-benzodiazepine-5-one,m.p. 220°-222° C.

EXAMPLE XV

The procedure of Example XIV is repeated except that an equivalentamount of each of3,4-dihydro-4-methyl-7-nitro-2-thio-1H-1,4-benzodiazepine-2,5-dione,3,4-dihydro-4-methyl-7-methyl-2-thio-1H-1,4-benzodiazepine-2,5-dione,3,4-dihydro-8-ethoxy-4-methyl-1H-1,4-benzodiazepine-2,5-dione issubstituted for the7-chloro-3,4-dihydro-4-methyl-2-thio-1H-1,4-benzodiazepine-2,5-dioneused therein, to yield, as respective products the following:

3,4-dihydro-2-[2-(3-indolylethyl)amino]-4-methyl-7-nitro-5H-1,4-benzodiazepine-5-one;

3,4-dihydro-2-[2-(3-indolylethyl)amino]-4-methyl-7-methyl-5H-1,4-benzodiazepine-5-one;

3,4-dihydro-8-ethoxy-2-[2-(3-indolylethyl)amino]-4-methyl-5H-1,4-benzodiazepine-5-one.

EXAMPLE XVI

A. β-Methyl-o-nitro-α-phenylhippuronitrile:

A solution of 92.78 g (0.5m) of o-nitro benzoyl chloride in 100 ml ofdry 1,2-dichloroethane is added dropwise over a 90 minute period to astirred, ice cooled solution of 73.10g (0.5m) of N-methyl-α-phenylglycinitrile and 55.66 g (0.55m) of triethylamine in 400 ml of dry1,2-dichloro-ethane. After stirring the reaction mixture for 4 1/2 hoursat room temperature, 200 ml of water is added. The layers are separatedand the organic layer is washed with two 150 ml portions of 1Nhydrochloric acid five 100 ml portions of 1N sodium hydroxide and two100 ml portions of saturated sodium chloride solution. The organic layeris dried and concentrated to dryness in vacuo to give an oily residue ofβ-methyl-o-nitro-α-phenyl hippuronitrile which may be used withoutfurther purification in the next step.

B.1-Hydroxy-2-imino-4-methyl-3-phenyl-1,2,3,4-tetrahydro-5H-1,4-benzodiazepine-5-onehydrochloride:

A solution of 14.77 g (0.05 m) of β-methyl-o-nitro-α-phenylhippuronitrile in 500 ml. of absolute ethanol containing 0.20 g ofplatinum oxide is hydrogenated at room temperature on a Parr shaker atan initial pressure of 50 psi. Hydrogen absorption is complete in about1 hour. The catalyst is removed by filtration, and the filtrateconcentrated to dryness in vacuo to given an impure solid. Triturationwith ether, fllowed by recrystallization from isopropanol gives thesolid,1-hydroxy-2-imino-4-methyl-3-phenyl-1,2,3,4-tetrahydro-5H-1,4-benzodiazepine-5-one.This is converted to the hydrochloride salt in ethanol. andrecrystallized from ethanol/ether (50 ml:200 ml) giving pure1-hydroxy-2-imino-4-methyl-3-phenyl-1,2,3,4-tetrahydro-5H-1,4-benzodiazepine-5-onehydrochloride, a solid, m.p. 223° C (dec.). Conventional treatment withalkali (e.g. dil. NaOH) affords the corresponding free base form.

C. 2-Amino-3,4-dihydro-4-methyl-3-phenyl-5H-1,4-benzodiazepine-5-one:

A slow stream of a solution of 23.00 g (0.132 m) of sodium dithionite in300 ml of water is added to a stirred solution of 16.87 g (0.06 m) of1-hydroxy-2-imino-4-methyl-3-phenyl-1,2,3,4-tetrahydro-5H-1,4-benzodiazepine-5-onein 700 ml of ethanol. The reaction mixture is refluxed for 2 hours andthen concentrated in vacuo, to about 200 ml. The resulting solution isextracted once with chloroform. Some solid crude product, formed duringthis extraction, is filtered off. The aqueous layer is made basic andextracted with chloroform. The organic solution are combined, dried andconcentrated to dryness in vacuo to give additional solid product. Thesolids are combined and recrystallized twice from ethanol/ether (thesolution is filtered while hot to clarify) to give the pure product,2-amino-3,4-dihydro-4-methyl-3-phenyl-5H-1,4-benzodiazepine-5-one m.p.282°-286° C.

EXAMPLE XVII

A. The procedure of Example XVI-A is repeated except that an equivalentamount each of the following compounds are used in place ofN-methyl-α-phenylglycinitrile used therein:N-methyl-α-(2,4,6-trichlorophenyl)glycinitrile,N-methyl-α-(3,4-dimethoxyphenyl)glycinitrile,N-methyl-α-(2-bromo-4-methylphenyl)glycinitrile, andN-ethyl-α-(4-trifluoromethylphenyl)glycinitrile to yield the followingas respective products:

β-methyl-o-nitro-α-(2,4,6-trichlorophenyl)hippuronitrile;

β-methyl-o-nitro-α-(3,4-dimethoxyphenyl)hippuronitrile;

β-methyl-o-nitro-α-(2-bromo-4-methylphenyl)hippuronitrile;

β-ethyl-o-nitro-α-(4-trifluoromethylphenyl)hippuronitrile.

B. An equivalent amount of each of the foregoing precursors issubstituted for the α-phenyl derivative used in Example XVI-B to producethe corresponding 3-substituted-phenyl intermediates.

C. These 3-substituted phenyl intermediates, each used in an equivalentamount as the1-hydroxy-2-imino-4-methyl-3-phenyl-1,2,3,4-tetrahydro-5H-1,4-benzodiazepine-5-oneof Example XVI-C, produce the corresponding 3-substituted phenyl endproducts.

EXAMPLE XVIII

A. β-Methyl-o-α-phenyl hippuric acid:

A solution of 92.78 g (0.5 m) of o-nitrobenzoyl chloride in 150 ml ofchloroform is added dropwise to a vigorously stirred solution of 100.87g (0.5 m) of α-phenyl sarcosine HCl and 40.00 g (1.0 m) of sodiumhydroxide in 750 ml of water while cooling in an ice bath. The reactionmixture is stirred for 5 hours at room temperature while periodicallyadding 5N sodium hydroxide solution (150 ml used) to keep the reactionbasic. The precipitated solid is then removed by filtration and theresulting layers are separated. The aqueous layer is cooled, acidifiedwith concentrated hydrochloric acid, and extracted with ethyl acetate.The ethyl acetate solution is dried and concentrated to dryness invacuo. The resulting solid is triturated with ether/hexane (200 ml / 100ml) and filtered to give the solid product β-methyl-o-nitro-α-phenylhippuric acid, m.p. 170°-179° C.

B. 3,4-Dihydro-4-methyl-3-phenyl-1H-1,4-benzodiazepine-2,5-dione:

A mixture of 47.2 g (0.15 m) of β-methyl-o-nitro-α-phenyl hippuric acidand 1.0 g of platinum oxide in 750 ml of 95% ethanol is hydrogenated ina Parr Hydrogenator, with cold water in the cooling jacket, at aconstant pressure of 20 psi for 1 hour and at a constant pressure of 30psi for 1/2 hour. The catalyst is filtered away and the filtrate isconcentrated almost to dryness in vacuo to give an oily residue. The oilis then dissolved in 150 ml of dimethylformamide and boiled down to 75ml. The addition of 25 ml of water and cooling causes the product,3,4,-dihydro-4-methyl-3-phenyl-1H-1,4-benzodiazepine-2,5-dione tocrystallize, having a m.p. of 242°-243° C. Recrystallization fromdimethylformamide/water gives a pure product,3,4-dihydro-4-methyl-3-phenyl-1H-1,4-benzodiazepine-2,5-dione, m.p.242°-244° C.

C. 3,4-Dihydro-4-methyl-3-phenyl-2-thio-1H-1,4-benzodiazepine-2,5-dione:

A mixture of 26.63 g (0.10 m) of3,4-dihydro-4-methyl-3-phenyl-1H-1,4-benzodiazepine-2,5-dione and 4.67 g(0.021 m) of phosphorous pentasulfide in 250 ml of pyridine are stirredand heated to reflux for 1 1/2 hr. 150 ml of pyridine is distilled offand then the reaction mixture is refluxed for 1 1/2 hr. more. The hotreaction mixture is added to 150 ml hot water and the mixture is stirredfor 1/2 hr. The precipitate is removed by filtration, washed with waterand dried to give the solid product3,4-dihydro-4-methyl-3-phenyl-2-thio-1H-1,4-benzodiazepine-2,5-dione,m.p. 250.5°-225° C.

D.3,4-Dihydro-4-methyl-2-methylthio-3-phenyl-5H-1,4-benzodiazepin-5-one:

A solution of 10.10 g (0.08 m) of dimethyl sulfate in 40 ml of methanolis added dropwise at room temperature to a stirred mixture of 22.59 g of3,4-dihydro-4-methyl-3-phenyl-2-thio-1H-1,4-benzodiazepine-2,5-dione, 80ml of 1N sodium hydroxide solution and 40 ml of methanol. The reactionmixture is stirred at room temperature for 5 hours, cooled in ice andthe pH adjusted to about 11 with 10N sodium hydroxide solution. Theprecipitate is removed by filtration, washed with water and dried togive 22.42 g of solid3,4-dihydro-4-methyl-2-methylthio-3-phenyl-5H-1,4-benzodiazepine-5-one,m.p. 130°-132° C.

E.3,4-Dihydro-4-methyl-2-phenethylamino-3-phenyl-5H-1,4-benzodiazepine-5-one:

A mixture of 7.41 g (0.025 m) of3,4-dihydro-4-methyl-2-methylthio-3-phenyl-5H-1,4-benzodiazepine-5-oneand 12.11 g (0.100 m) of phenethylamine is heated in an oil bath for 6hours. The temperature of the oil bath is slowly raised to 240° C andheld there for 1 hour. After cooling to room temperature, the residualoil is crystallized from ether to give the crude product,3,4-dihydro-4-methyl-2-phenethylamino-3-phenyl-5H-1,4-benzodiazepine-5-one.Recrystallization from ethyl acetate and ethyl acetate-ether gives apure product,3,4-dihydro-4-methyl-2-phenethylamino-3-phenyl-5H-1,4-benzodiazepine-5-one,a white solid, m.p. 173°-174.5° C.

EXAMPLE XIX3,4-Dihydro-2-[2-(dimethylamino)ethylamino]-4-methyl-3-phenyl-5H-1,4-benzodiazepine-5-oneDihydrochloride Hemihydrate:

A mixture of 8.48 g (0.03 m) of3,4-dihydro-4-methyl-3-phenyl-2-thio-1H-1,4-benzodiazepine-2,5-dione and13.20 g (0.15m) of β-dimethylaminoethylamine are heated in an oil bathat 145±5° C under reflux for 25 minutes. The excess amine is removed invacuo at 100° C and the residue is triturated with ether to give solid3,4-dihydro-2-[2-(dimethyl-amino)ethylamino]-4-methyl-3-phenyl-5H-1,4-benzodiazepine-5-onedihydrochloride hemihydrate, m.p. (240°) 246°-250° C (dec).

What is claimed is:
 1. A compound selected from the group consisting ofa 2-aminobenzodiazepine-5-one of the formula: ##STR8## and thetherapeutically active non-toxic acid addition salts thereof, wherein:Ris a member selected from the group consisting of hydrogen,arylloweralkyl, indolylloweralkyl, diloweralkylaminoloweralkyl and aryl;R₁ is a member selected from the group consisting of hydrogen and aryl;R₂ is loweralkyl; and R₃ is a member selected from the group consistingof hydrogen, halo, nitro, loweralkoxy and loweralkyl; provided, that,when R is hydrogen, then said R₁ is aryl; the aforementioned term arylin each occurrence being a member selected from the group consisting ofphenyl, trifluoromethylphenyl and phenyl substituted with from 1 to 3members selected from the group consisting of halo, loweralkyl, hydroxy,and loweralkoxy.
 2. A compound selected from the group consisting of a2-aminobenzodiazepine-5-one of the formula: ##STR9## and thetherapeutically active non-toxic acid addition salts thereof, wherein:Ris a member selected from the group consisting of hydrogen,arylloweralkyl, indolylloweralkyl, diloweralkylaminoloweralkyl and aryl,said aryl in each occurrence being a member selected from the groupconsisting of phenyl, trifluoromethylphenyl and phenyl substituted withfrom 1 to 3 members selected from the group consisting of halo,loweralkyl, hydroxy and loweralkoxy; R₁ is a member selected from thegroup consisting of hydrogen and phenyl; R₂ is methyl; and R₃ is amember selected from the group consisting of hydrogen and chloro;provided that, when said R is hydrogen, then said R₁ is phenyl.
 3. Acompound selected from the group consisting of2-benzylamino-7-chloro-3,4-dihydro-4-methyl-5H-1,4-benzodiazepine-5-oneand the therapeutically active non-toxic acid addition salts thereof. 4.A compound selected from the group consisting of3,4-dihydro-4-methyl-2-β-phenethylamino-5H-1,4-benzodiazepine-5-one andthe therapeutically active non-toxic acid addition salts thereof.
 5. Acompound selected from the group consisting of7-chloro-3,4-dihydro-4-methyl-2-phenethylamino-5H-1,4-benzodiazepine-5-oneand the therapeutically active nontoxic acid addition salts thereof. 6.A compound selected from the group consisting of7-chloro-3,4-dihydro-2-(2,3-dimethoxy-β-phenethylamino)-4-methyl-5H-1,4-benzodiazepine-5-oneand the therapeutically active non-toxic acid addition salts thereof. 7.A compound selected from the group consisting of3,4-dihydro-2-(3,4-dihydroxyphenethylamino)-4-methyl-5H-1,4-benzodiazepine-5-oneand the therapeutically active non-toxic acid addition salts thereof. 8.A compound selected from the group consisting of7-chloro-2-(2',6'-dichloroanilino)-3,4-dihydro-4-methyl-5H-1,4-benzodiazepine-5-oneand the therapeutically active non-toxic acid addition salts thereof. 9.A compound selected from the group consisting of7-chloro-3,4-dihydro-2-[3-(dimethylamino)propylamino]-4-methyl-5H-1,4-benzodiazepine-5-oneand the therapeutically active non-toxic acid addition salts thereof.10. A compound selected from the group consisting of7-chloro-3,4-dihydro-2-[2-(3-indolylethyl)amino]-4-methyl-5H-1,4-benzodiazepine-5-oneand the therapeutically active non-toxic acid addition salts thereof.11. A compound selected from the group consisting of2-amino-3,4-dihydro-4-methyl-3-phenyl-5H-1,4-benzodiazepine-5-one andthe therapeutically active non-toxic acid addition salts thereof.
 12. Acompound selected from the group consisting of3,4-dihydro-4-methyl-2-phenethylamino-3-phenyl-5H-1,4-benzodiazepine-5-oneand the therapeutically active nontoxic acid addition salts thereof. 13.A compound selected from the group consisting of3,4-dihydro-2-[2-(dimethylamino)ethylamino]-4-methyl-3-phenyl-5H-1,4-benzodiazepine-5-oneand the therapeutically acitve non-toxic acid addition salts thereof.